Abstract Rationale Pulmonary hypertension (PH) is a frequent and severe complication in chronic lung disease (CLD), although its potential genetic determinants are poorly defined. This study aimed to characterize the genetic landscape of PH associated with chronic obstructive pulmonary disease (COPD) and fibrosing interstitial lung disease (ILD), in comparison with idiopathic pulmonary arterial hypertension (iPAH), using a targeted sequencing approach. Methods We analyzed 114 patients with CLD: 36 without PH (17 COPD, 19 ILD), 33 with non-severe PH (18 COPD, 15 ILD) and 45 with severe PH (28 COPD, 17 ILD); and 38 with iPAH. A custom panel of 150 genes, prioritized through lung-specific interactome analysis and literature review, was sequenced in DNA isolated from peripheral blood mononuclear cells. The prevalence of pathogenic (P), likely pathogenic (LP), and variants of uncertain significance (VUS) present in patients with PH, but not in patients with CLD without PH, was analyzed. Results Regarding genes with established association to PAH, 5 patients with iPAH (13.1%) showed P variants in genes BMPR2 (n = 3), ACVRL1 (n = 1), and TOPBP1 (n = 1). Three patients with severe COPD-PH (10.7%) showed VUS in genes BMPR2 (n = 1) and BMPR1B (n = 2), and one patient with non-severe ILD-PH (6.7%) showed a VUS in SMAD9 gene. Regarding other genes analyzed in the panel, eight patients with iPAH (21%) showed VUS in genes CYP1B1 (n = 3), NCOR2 (n = 2), PTGS2 (n = 2), and PTK2 (n = 1). Five patients with severe COPD-PH (17.8%) harbored VUS in genes THBS1 (n = 2), C3 (n = 2), LOXL2 (n = 2), and PTK2 (n = 1); no variants were found in non-severe COPD-PH. Two patients with severe ILD-PH (11.7%) harbored variants in genes C3 and TNFAIP6 (n = 1, each); and one patient with non-severe ILD-PH (6.7%) harbored the same VUS in TNFAIP6 gene. Variants exclusively present in severe CLD-PH were found in genes involved in matrix remodeling and inflammation. Conclusions Whereas pathogenic variants in PAH-associated genes were detected only in iPAH, some patients with severe CLD-PH also exhibited VUS in these genes, suggesting a potential role in the development of severe PH. Furthermore, we identified gene variants exclusive to severe CLD-PH that have not been previously associated with PH. Functional validation is necessary to confirm their contribution to disease pathophysiology and to assess their potential as biomarkers or therapeutic targets. This abstract is funded by: PI18/00383 (ISCiii) and FCHP
Armora et al. (Fri,) studied this question.